Institute for Genome Research of The University ofTokushima aims to elucidate the principles of unified
biological systems and the mechanisms of diseases.
Division of Immune Regulation, Professor Taku Okazaki
TEL +81-88-633-9160
E-MAIL tokazaki@genome.tokushima-u.ac.jp
Division of Genome Medicine, Professor Toyomasa Katagiri
TEL +81-88-633-9477
E-MAIL tkatagi@genome.tokushima-u.ac.jp

Institute for Genome Research
The University of Tokushima

Division of Molecular Biology, Professor Seiichi Oyadomari
TEL +81-88-633-9450
E-MAIL oyadomar@genome.tokushima-u.ac.jp
Division of Protein Expression, Professor Yasuo Shinohara
TEL +81-88-633-9145
E-MAIL yshinoha@genome.tokushima-u.ac.jp
Division of Genetic Information, Professor Mitsuo Itakura
TEL +81-88-633-9454
E-MAIL itakura@genome.tokushima-u.ac.jp
Division of Experimental Immunology, Professor andDirector Yousuke Takahama
TEL +81-88-633-9452
E-MAIL takahama@genome.tokushima-u.ac.jp

AccessResearch 2008-2009
Human genome sequence was determined.
It is now essential to clarify biological functions of
the genome, especially focusing on genome
functions associated with human diseases.
Institute for Genome Research (IGR) of
The University of Tokushima, originally founded
in 1998, has been renewed on April1, 2008.

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International Airport

The IGR aims to elucidate the principles of unified
biological systems and the mechanisms of diseases.

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The IGR is fully aware of the importance ofcollaborations with various academic,

Haneda Airport
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governmental, and industrial institutions. The IGR
is also firmly committed to the education at
graduate and undergraduate schools at The

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University of Tokushima.

Domestic airline 70mins

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Institute for Genome Research
The University of Tokushima
3-18-15, Kuramoto, Tokushima 770-8503, JAPANTEL +81-88-633-9420 FAX +81-88-633-9422
http://www.genome.tokushima-u.ac.jp

Institute for Genome Research, The University of Tokushima

Immune Regulation / Genome Medicine

Section of Genomics
Division of Immune Regulation
Genetic dissection and reconstitution of
autoimmune diseases
Most of the autoimmune diseases are polygenic disease and many genetic
polymorphisms are involved in the development and the progression of the disease.
Thanks to the recent advancement in the genetic engineering, many genes have been
identified and their functions in the immune system have been vigorously analyzed.
However, it is largely unknown which genes are really involved and how multiple genes
collaborate in the regulation of autoimmune diseases. We are trying to identify
autoimmune susceptible genes comprehensively by genetically dissecting autoimmune
susceptible mice and analyze their synergistic function to fully understand the molecularmechanisms of immunological tolerance.
Although genetic linkage analyses have been widely employed on both humanpatients and model animals, responsible genes have hardly been identified. The
involvement of too many genes and the weak influence of individual gene are supposed
to be the main cause of the difficulty. We are trying to overcome this difficulty by using
PD-1 deficient mice that develop different type of autoimmune disease on different
genetic background.
Mice deficient for PD-1 gene develop lupus-like glomerulonephritis on C57BL/6
background and autoimmune dilated cardiomyopathy on BALB/c background. When we
introduced PD-1 deficiency on NOD mice, which spontaneously develop type I diabetes.
NOD-PD-1-/- mice developed diabetes much earlier and completely (from 4 weeks ofage, 100% by 8 weeks of age) compared to NOD-wild type mice (from 15 weeks ofage, 40-70% by 30 weeks). Because the quick and the complete incidence of diabetes
were supposed to assure more sensitive and accurate genetic linkage analyses, we
performed genetic linkage analyses using intercross progenies of NOD-PD1-/- mice and
C57BL/6-PD-1-/- mice. Among 26 known diabetes susceptible loci, only 2 loci showedsignificant association to the diabetic incidence. Moreover, dominant susceptible genes
could not be analyzed with NOD-wild type mice because of the low incidence ofdiabetes in F2 intercross progenies. In virtue of PD-1 deficiency, we could also screen
dominant diabetes susceptible loci throughout genome and identified two new loci andnamed these as Iddp1 and Iddp2. These results suggest that diabetic incidence on NODPD-1-/- mice can be explained only by 5 genes including PD-1, which is a great
advancement compared to the 26 genes. We are currently trying to generate C57BL/6congenic mice, which develop diabetes spontaneously by introducing NOD-derived
chromosomal fragments.
On the other hand, inhibition of immune responses by PD-1 may dampen beneficial
tumor immunity or anti-infectious immunity. We have found that cancer cells and viral
infected cells express ligands of PD-1 and induce paralysis of anti-tumor or anti-viral
immune responses. Therefore, we are trying to develop methods to block PD-1dependent immune suppression to treat cancer and infectious diseases.

tokazaki@genome.tokushima-u.ac.jp

Taku Okazaki M.D., Ph.D.

Toyomasa Katagiri Ph.D.

1993-1999
1999-2004

1991
1991-1992
1992-1995

2000-2004
2004
2004-2008

2008-

Faculty of Medicine, Kyoto University
Department of Medical Chemistry, Graduate Schoolof Medicine, Kyoto University
JSPS fellow
Assistant Professor, Department of Medical Chemistry,
Graduate School of Medicine, Kyoto University
COE Associate Professor, 21st Center of Excellence
Formation, Graduate School of Medicine, Kyoto
University
Professor, Division of Immune Regulation, Institutefor Genome Research, University of Tokushima

Assistant Professor : Il-mi Okazaki Ph.D.

The determination of human genome sequence has been completed on April 2003 as a result of
human genome project. Thus, it is now crucial to clarify the function of genes in the genome.
Particularly functional analysis of genes associated with human diseases, especially human cancer is amatter of great importance for development of novel diagnostic and therapeutic tools.
Our division was launched in May 2008. The major goal of our division is to identify genes which
are involved in carcinogenesis, and to develop novel diagnostic and therapeutic strategies. We havebeen attempting to identify genes involved in carcinogenesis by means of technologies developed
through genome-wide cDNA microarray and SNP-analyses (Fig.1). We have been working on thefollowing major projects;
1) Characterization and identification of molecular-targets for novel diagnostic and therapeutic drugs
for cancer therapy,2) Investigation of mechanisms underlying triple-negative breast cancer (estrogen receptor-negative,
progesterone-negative and Her2-negative)

Kido M, Watanabe N, Okazaki T, Akamatsu T, Tanaka J, Saga K, Nishio A, Honjo T,
Chiba T.
Fatal autoimmune hepatitis induced by concurrent loss of naturally arising regulatory T
cells and PD-1 mediated signaling.
Gastroenterology. 135:1333-1343 (2008)
Yoshida T, Jiang F, Honjo T, Okazaki T.
PD-1 deficiency reveals various tissue-specific autoimmunity by H-2b and dosedependent requirement of H-2g7 for diabetes on NOD background.
Proc Natl Acad Sci USA. 105:3533-3538 (2008)

Okazaki T, Tanaka Y, Nishio R, Mitsuiye T, Mizoguchi A, Wang J, Ishida M, Hiai H,
Matsumori A, Minato N, Honjo T.
Autoantibodies against cardiac troponin I are responsible for the dilated cardiomyopathy
in PD-1 deficient mice.
Nature Med. 9:1477-1483 (2003)

Institute for Genome Research, The University of TokushimaMSc, Faculty of Agriculture, Kagawa University
Research Associate, Otsuka Pharmaceutical Co., Ltd..
Research Associate, Department of Biochemistry, Cancer Institute,Japanese Foundation for Cancer Research.
1995-1998 Research Associate, Department of Human Genome Analysis, theCancer Chemotherapy Center, Japanese Foundation for Cancer
Research.
1998
PhD, Medical School, Osaka University.
1998-2001 Postdoctoral Fellow, Department of Medical and Molecular Genetics,
Division of Genetics and Development, Guy's Kings and St Thomas'
School of Medicine, King's College London.
2001-2004 Assistant Professor, Human Genome Center, Institute of Medical
Science, The University of Tokyo.
2004-2008 Associate Professor, Human Genome Center, Institute of Medical
Science, The University of Tokyo.
2008-present Professor, Division of Genome Medicine, Institute for Genome
Research, The University of Tokushima.

Characterization and identification of novel
molecular-targets for cancer therapy thoughhuman genome analysis

Okazaki T, Honjo T.
Rejuvenating exhausted T cells during chronic viral infection.
Cell. 122:459-461 (2006)

2

tkatagi@genome.tokushima-u.ac.jp

Assistant Professor : Taisuke Matsuo M.Sc.

Fig.1
NOD.H2b.PD-1-/- mice develop peripheral
polyneuropathy similar to human GuillainBarré syndrome and chronic inflammatory
demyelinating polyneuropathy.

Fig.2
Blockade of PD-1 signaling leads to theeradication of tumor cells and clearance of
pathogens. While enhancement of PD-1
signaling can be applied to autoimmunity,
allergy, and transplant rejection.

Division of Genome Medicine

1. Characterization and identification of novel molecular-targets for the diagnosis andtreatment of human cancers
To identify novel molecular-targets for the diagnosis and treatment of cancer, we have been analyzing
the gene expression profiles in breast cancers, renal cell carcinomas and bladder cancers as well as
normal human tissues by means of cDNA microarray in collaboration with Prof. Yusuke Nakamura’slaboratory in Institute of Medical Science, the University of Tokyo. Through these microarray data, wehave identified several candidate genes that are overexpressed in cancer cells and not expressed innormal human organs, especially vital organs, as novel molecular targets for therapeutic drugs(compounds, antibody drugs or RNAi drugs), and/or diagnosis of human cancers. Particularly,
through analysis of breast cancer expression profile, we focused on, PBK/TOPK (PDZ-binding kinase/TLAK cell-originated protein kinase), as a drugable target molecule. The expression of this gene was
highly and frequently upregulated in breast cancer specimens, but not or undetectable in normal vitalorgans. Knocking down of PBK/TOPK expression by siRNA resulted in significant suppression of breast
cancer cell growth (Fig. 2). Furthermore, we demonstrated that PBK/TOPK could phosphorylate
histone H3 as a substrate, at Ser10 in vitro and in vivo, and mediated its growth-promoting effectthrough histone H3 modification. Currently, we are studying the functional analysis of several target
molecules involved in carcinogenesis including PBK/TOPK for cancer therapy in clinical use.
2. Investigation of mechanisms underlying triple-negative breast cancer (ER-negative, PgRnegative and Her2-negative)
Triple-negative breast cancers (TNBC) are defined by a lack of estrogen, progesterone, and Her2
receptors. TNBC has distinct clinical and pathologic features, and is a clinical problem because of its
relatively poor prognosis, aggressive behavior and lack of targeted therapies, leaving chemotherapy as
the mainstay of treatment. We are aiming at understanding molecular mechanism of TNBC
carcinogenesis, and identifying therapeutic-targets for effective treatment of TNBC.

Fig.1. Development of strategies for better diagnosis, effective
treatment and prevention oh human cancer on the basis ofhuman genome analysis.

Fig.2 (left panles) PBK/TOPK expression pattern in breast
cancer and normal human tissues. (right panels) Growth
inhibitory effects of PBK/TOPK-siRNAs in breast cancer cell.
Fukukawa C, Nagayama S, Tsunoda T, Toguchida J, Nakamura Y, Katagiri T.
Activation of non-canonical Dvl-Rac1-JNK pathway by Frizzledhomologue 10 (FZD10) in human synovial sarcoma.
Oncogene. 28:1110-1120 (2009)
Kanehira M, Katagiri T, Shimo A, Takata R, Shuin T, Miki T, Fujioka T, Nakamura Y.
Oncogenic role of MPHOSPH1, a cancer-testis antigen specific to human
bladder cancer.
Cancer Res. 67:3276-3285 (2007)
Park JH, Lin ML, Nishidate T, Nakamura Y, Katagiri T.
PDZ-binding kinase/T-LAK cell-originated protein kinase, a putativecancer/testis antigen having an oncogenic activity in breast cancer.
Cancer Res. 66:9186-9195 (2006)
Togashi A, Katagiri T, Ashida S, Fujioka T, Maruyama O, Wakumoto Y,
Sakamoto Y, Fujime M, Kawachi Y, Shuin T, Nakamura Y.
Hypoxia-inducible protein 2 (HIG2), a novel diagnostic marker for renal
cell carcinoma (RCC) and potential target for molecular therapy.
Cancer Res. 65:4817-4826 (2005)
Miki Y, Katagiri T, Kasumi F, Yoshimoto T, Nakamura Y
Mutation analysis in the BRCA2 gene in primary breast cancers.
Nature Genet. 13:245-247 (1996)

Institute for Genome Research, The University of Tokushima

3

Institute for Genome Research, The University of Tokushima

Molecular Biology / Protein Expression

Section of Proteomics
Division of Molecular Biology
Role of endoplasmic reticulum stressresponse in metabolism regulation
We are in the post-genome era but, in reality, have not reached to utilize theemerging genetic and genomic knowledge for establishing personalized medicine. The
revolution in genome research has provided us with a unique perspective on humanhealth and disease susceptibility. It has proven, however, enormously more complex
than at first thought. We must intensify research efforts on exploration of gene function
and molecular pathogenesis. Our research focus is to tackle the issues from the pointview of endoplasmic reticulum stress response (ER stress response) with a hope tocontribute to develop new therapeutic strategies to treat diseases.
Endoplasmic reticulum (ER) is the site of synthesis and folding of secretory proteins.
Perturbations of ER homeostasis affect protein folding and cause ER stress. ER can sense
the stress and respond to it through gene expression program so called ER stressresponse. The ER stress response has four functional components (Figure). The first istranslational attenuation, which inhibits protein synthesis, an adaptation aimed atlowering the load of client proteins the ER must process. The second is thetranscriptional upregulation of the folding machineries in the ER to process client
proteins. The third is enhancing degradation of misfolded protein in the ER, which iscalled ER-associated degradation (ERAD). The fourth is apoptosis, which occurs when
the ER function is severely impaired. ER stress response is important for normal cellular
homeostasis and development and suggested to involve in the pathogenesis of many
diseases. We have shown that pancreatic beta-cells (which produce the hormone
insulin) are highly susceptible to ER stress and mal-adaptation to ER stress causes
diabetes.
Diabetes is emerging as one of the most serious health problems in the world.
Diabetes develops when a critical number of pancreatic beta-cells become damaged ordie. We speculate that ER stress is occurred in pancreatic beta-cells by overworking andoverproducing insulin in pre-diabetic obesity. The high levels of ER stress for long time
will lead pancreatic beta-cells into exhaustion or death. We hypothesize ER stress may
be main contributor to the development of diabetes. The long-term goal of our researchis to understand the role of ER stress response in metabolism regulation and to integratethese into an understanding of the pathogenesis of diabetes and other ER stress-relateddiseases. We expect that our work may eventually provide new targets for prevention
and treatment of diabetes, as well as other ER stress-related disease. We are welcoming
everyone who is interested in joining us in our endeavor to unravel the great mystery ofnature.

oyadomar@genome.tokushima-u.ac.jp

1995
1997
2001
2001
2002
2003
2004

M.D. Kumamoto University School of Medicine
Internal Medicine Resident, Kumamoto University Hospital
Ph.D.(Doctorate of Medical Science), Graduate School of Medical
Sciences, Kumamoto University
Clinical Fellow, Department of Metabolic Medicine, Kumamoto
University
Research Fellow, Department of Molecular Genetics, Kumamoto
University
Research Fellow, Skirball Institute of Biomolecular Medicine, NewYork University School of Medicine
Professor, Institution for Genome Research, The University ofTokushima

1990

Ph.D., Graduate School of Pharmaceutical Sciences, Universityof Tokushima
1990-1993 Assistant Professor, Faculty of Pharmaceutical Sciences,
University of Tokushima
1993-2002 Associate Professor, Faculty of Pharmaceutical Sciences,
University of Tokushima
1994
Visiting Scientist, E.C. Slater Institute, University of Amsterdam
2002-present Professor, Institute for Genome Research and Faculty of
Pharmaceutical Sciences, University of Tokushima
2002-present Invited Researcher, National Institute of Advanced Industrial
Science and Technology (AIST)
Assistant Professor : Takenori Yamamoto Ph.D.

Control of cellular fate and energy
metabolism

Oyadomari S, Mori M.
Roles of CHOP/GADD153 in endoplasmic reticulum stress.
Cell Death Differ. 11: 381-389 (2004)
Oyadomari S, Koizumi A, Takeda K, Gotoh T, Akira S, Araki E, Mori M.
Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediateddiabetes.
J Clin Invest. 109: 525-532 (2002)

Institute for Genome Research, The University of Tokushima

Yasuo Shinohara Ph.D.

Assistant Professor : Keisuke Yamamoto Ph.D.

Oyadomari S, Yun C, Fisher EA, Kreglinger N, Kreibich G, Oyadomari M, Harding HP,
Goodman AG, Harant H, Garrison JL, Taunton J, Katze MG, Ron D.
Cotranslocational degradation protects the stressed endoplasmic reticulum from protein
overload.
Cell. 2006 126: 727-739 (2006)

4

yshinoha@genome.tokushima-u.ac.jp

Seiichi Oyadomari M.D., Ph.D.

Oyadomari S, Harding HP, Zhang Y, Oyadomari M, Ron D.
Dephosphorylation of translation initiation factor 2alpha enhances glucose tolerance andattenuates hepatosteatosis in mice.
Cell Metabolism. 7: 520-532 (2008)

The functional components of the ER stress response. Accumulation of unfolded proteins in the ER activates four cellularresponses.

Division of Protein Expression

Oyadomari S, Takeda K, Takiguchi M, Gotoh T, Matsumoto M, Wada I, Akira S, Araki E,
Mori M.
Nitric oxide-induced apoptosis in pancreatic beta cells is mediated by the endoplasmic
reticulum stress pathway.
Proc Natl Acad Sci U S A. 98: 10845-10850 (2001)

Our major research interests are regulatory mechanisms of the energy
metabolism and programmed cell death. Especially, we are studying two research
projects of i) structure and function of mitochondria and ii) energy metabolism
specifically occurring in adipose tissues.
As for the first research topics, we are interested in the status of mitochondrial
inner membrane. Under the ordinary physiological conditions, permeability of
inner mitochondrial membrane is kept very low, to enable effective energy
conversion.
However, under certain conditions, permeability of innermitochondrial membrane is known to be remarkably elevated. The physiologicalmeanings of this increase in the permeability of inner mitochondrial membrane
have been uncertain, however, recent studies indicated that it is associated withthe release of mitochondrial cytochrome c, and regulation of programmed cell
death. Thus, we are studying the relationship between the status of innermitochondrial membrane and release of mitochondrial cytochrome c. Our recent
studies revealed that cytochrome c could be released from mitochondria
accompanied with or without changes in the permeability of mitochondrial inner
membrane. These distinct mechanisms causing release of cytochrome c were also
successfully explained by proteomics analysis.
As for the latter research topics, we have been studied the molecular basis of
the thermogenic function occurring in brown adipose tissue. Of two kinds ofadipose tissues present in mammals (brown and white adipose tissues, abbreviatedas BAT and WAT, respectively), only BAT exerts thermogenic function. Thus, tovisualize the molecular basis enabling thermogenesis in BAT, we compared gene
expression profiles between BAT and WAT. As a result, genes preferentiallyexpressed in BAT were found to be similar to those expressed in skeletal muscle
rather than those in WAT. Thus, we concluded that metabolisms occurring in BAT
and suitable for thermogenesis are similar to those occurring in skeletal muscle.
We also started to identify and characterize the genes preferentially expressed in
WAT.

Fig. 1
Proteomics studies on the three voltage dependent anion channel (VDAC)
isoforms expressed in mitochondria
Fig. 2
Changes in the gene expression inbrown adipose tissue induced by cold
exposure of experimental animals

Yamada A, Yamamoto T, Yamazaki N, Yamashita K, Kataoka M, Nagata T, Terada H,
Shinohara Y.
Differential permeabilization effects of Ca2+ and valinomycin on the inner and outer mitochondrial
membranes as revealed by proteomics analysis of proteins released from mitochondria
Mol Cell Proteomics. in press (2009)
Yamamoto T, Yoshimura Y, Yamada A, Gouda S, Yamashita K, Yamazaki N, Kataoka M,
Nagata T, Terada H, Shinohara Y.
Distinct behaviors of adenylate kinase and cytochrome c observed following induction of
mitochondrial permeability transition by Ca2+ in the absence of respiratory substrate
Bioenerg Biomemb. 40:619-623 (2008)
Watanabe M, Yamamoto T, Kakuhata R, Okada N, Kajimoto K, Yamazaki N, Kataoka M, Baba Y,
Tamaki T, Shinohara Y.
Synchronized changes in the transcript levels of the genes towards activated thermogenesis inbrown adipose tissue induced by cold exposure of experimental animals
Biochim Biophys Acta. 1777:104-112 (2008)
Yamamoto T, Yamada A, Watanabe M, Yoshimura Y, Yamazaki N, Yoshimura Y, Yamauchi T,
Kataoka M, Nagata T, Terada H, Shinohara Y.
VDAC1, having a shorter N-terminus than VDAC2 but showing the same migration as it in an
SDS-polyacrylamide gel, is the predominant form expressed in mitochondria of various tissues
J Proteome Res. 5:3336-3344 (2006)

Institute for Genome Research, The University of Tokushima

5Institute for Genome Research, The University of Tokushima

Genetic Information / Experimental Immunology

Section of Systems Biology
Division of Genetic Information
Genome analysis by correlating genetic
variants with phenotypes
1) Elucidation of etiologic genes responsible for congenital metabolic disorders:
We discovered etiologic genes for monongenic disorders by linkage analysis of theaffected pedigrees and positional cloning. We identified the etiologic mutations in the
UMOD (uromodulin) gene in Familial Juvenile Hyperuricemic Nephropathy. We
discovered splicing site mutations in the CSPGS (chondroitin sulfate proteoglycan) genein Wagner syndrome. We discovered GDD1 (TMEM16E) as the etiologic gene forGnatho-Diaphyseal Dysplasia. By using antibody for GDD1, we examined theintracellular localization and the presence of glycosylation of GDD1. By the in situ
hybridization, we examined the expression pattern of GDD1 in the early developmental
stages. The analysis of knockout mouse is under way.

itakura@genome.tokushima-u.ac.jp

Division of Experimental Immunology

takahama@genome.tokushima-u.ac.jp

Mitsuo Itakura M.D., Ph.D.
1973
1973-1975
1976-1977
1977
1977-1980
1980
1980-1990

M.D. the University of Tokyo, School of Medicine.
Internal Medicine Resident, Tokyo University Hospital
Research Fellow, Duke University Medical Center
Clinical Fellow, Duke University Medical Center
Research Fellow, Duke University Medical Center
Research Associate, Duke University Medical Center
Assistant Professor, Division of Endocrinology and Metabolism,
Institute for Clinical Medicine, Tsukuba University
1995-1996 Visiting Professor, Division of Endocrinology, Metabolism, andGenetics, Duke University Medical Center
1990-2000 Visiting Professor, Otsuka Department of Clinical andMolecular Nutrition, The University of Tokushima.
1998-2008 Professor and Director, Division of Genetic Information, Institutefor Genome Research, The University of Tokushima
2008-now Professor, Division of Genetic Information, Institute for Genome
Research, The University of Tokushima

Yousuke Takahama Ph.D.
1982
1988
1988-1989
1989-1992

B.S., Tokyo Institute of Technology
Ph. D., Osaka University Medical School
Research Fellow, Osaka University Medical School
Visiting Fellow, National Cancer Institute, National
Institutes of Health
1992-1993 Visiting Associate, National Cancer Institute, National
Institutes of Health
1993-1995 Research Group Leader, Syntex Institute of
Immunology
1995-1999 Assistant Professor, Institute of Basic Medical
Sciences, University of Tsukuba
1997-2000 PRESTO Investigator, Japan Science and Technology
Corporation
2001-2003 Team Director, RIKEN Center for Allergy and Immunology
1999-present Professor, Institute for Genome Research, Universityof Tokushima
2008-present Director, Institute for Genome Research, University ofTokushima

Associate Professor : Hiroshi Inoue M.D., Ph.D.

2) Identification of susceptibility genes for type 2 diabetes and rheumatoid arthritis:
We collected genomic DNA and established immortalized lymphoblast cell lines from
more than 1,000 subjects each with type 2 diabetes or rheumatoid arthritis, and from1,600 healthy control subjects. We examined minor allele frequency of about 90,000
SNPs in Japanese (http://www.genome.tokushima-u.ac.jp/dgi/ENGDGI/ASNPs_E/index_
English.html). By 5 chromosome-wide association studies on 1,500~2,000 subjects with
T2D based on the replicated candidate chromosomal regions by affected sib pairanalysis, we found ENDOGL1, SOCS2 as the candidate susceptibility gene for T2D. By
the chromosome-wide analysis on rheumatoid arthritis, we have extracted EXOC4(SEC8L1) and PRKCH gene as the candidate gene for rheumatoid arthritis in Japanese.
We are now analyzing the genetic basis of children with short stature by the mutation
analysis and CNV (copy number variation) analysis.

Assistant Professor : Tomoo Ueno Ph.D.
Assistant Professor : Takeshi Nitta Ph.D.

Towards understanding how
immune system is established

3) QTL analysis of F2 intercrosses between mice developing diabetes and thosewhich do not become diabetic:
By using the F2 generation between db mice with the deficiency of leptin receptor
and C3H or DBA2 mice, we identified 20 or 27 QTLs. We made congenic mice between
db and DBA2 for 4 QTL loci and one locus at chromosome 5 was shown to reproduce
the phenotypes including body weight, intestinal fat amount, and others in F2
intercross. We identified the responsible gene for this phenotype and we are now
examining the function of this gene by transgenic and knockout mice technology withthe collaboration with Otsuka Pharmaceutical Company.
Based on the analysis on the genome function in humans and mice, we are trying tounderstand the disease mechanism relating with patho-physiology and metabolic
regulation.

Yasuda K, Miyake K, Horikawa Y, Hara K, Osawa H, Furuta H, Hirota Y, Mori H, Jonsson A,
Sato Y, Yamagata K, Hinokio Y, Wang HY, Tanahashi T, Nakamura N, Oka Y, Iwasaki N,
Iwamoto Y, Yamada Y, Seino Y, Maegawa H, Kashiwagi A, Takeda J, Maeda E, Shin HD,
Cho YM, Park KS, Lee HK, Ng MC, Ma RC, So WY, Chan JC, Lyssenko V, Tuomi T, Nilsson P,
Groop L, Kamatani N, Sekine A, Nakamura Y, Yamamoto K, Yoshida T, Tokunaga K,
Itakura M, Makino H, Nanjo K, Kadowaki T, Kasuga M.
Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus.
Nature Genet. 40:1092-1097 (2008)
Tanahashi T, Shinohara K, Keshavarz P, Yamaguchi Y, Miyawaki K, Kunika K, Moritani M,
Nakamura N, Yoshikawa T, Shiota H, Inoue H, Itakura M.
The association of genetic variants in Kruppel-like factor 11 and Type 2 diabetes in theJapanese population.
Diabet Med. 25:19-26 (2008)
Kunika K, Tanahashi T, Numata S, Ueno S, Ohmori T, Nakamura N, Tsugawa K,
Miyawaki K, Moritani M, Inoue H, Itakura M.
Common coding variant in the TCF7L2 gene and study of the association with type 2
diabetes in Japanese subjects.
J Hum Genet. 53:972-982 (2008)

Long-term goal of the laboratory is to unveil molecular mechanismthat is essential for establishing immune system. One of the mostprominent characteristics of the immune system is the discrimination offoreign substances from self-constituents, so that immune responses
would attack various pathogens while maintaining tolerance to theself.
T lymphocytes are the cells that play an essential role indistinguishing non-self from self. T lymphocytes acquire this ability
through shaping a repertoire of recognition specificity during thedevelopment in the thymus, by the process referred to as positive andnegative selection. Much has been revealed during the past two
decades how antigen-receptor signals in developing T lymphocytes
control the cells' fate upon positive and negative selection. However,
how T lymphocytes are generated and selected in the thymus
environment is still poorly understood.
Thus, our current interest is to understand molecular programs (1)that build up functionally competent thymus, which is capable ofsupporting and selecting T lymphocytes, (2) that position developing T
lymphocytes to localize within the thymus microenvironments forshaping T-lymphocyte repertoire, and (3) that control intrathymic
selection to generate a healthy pool of mature T lymphocytes.
Unveiling molecular machinery that is essential for establishing
functional thymus and T lymphocyte selection should aid controllingvariousimmunediseases
includingautoimmunty
andimmunodeficiencies.

Lymphostromal interactions in T-cell development and repertoire formation in
the thymus. Early development of lymphoidprogenitor cells to the CD4 and CD8 doublepositive (DP) thymocytes is supported incortical microenvironment. In the thymic cortex, thymic cortical epithelial cells (cTEC) support TCR-mediated positive and negative selection of DP thymocytes. Positively selected
thymocytes differentiate to CD4 or CD8 single-positive (SP) thymocytes and relocate to
the medulla through CCR7-mediated chemotactic attraction by thymic medullary epithelial cells (mTEC). In the medulla, mTEC, alongwith DC, establish negative selection of selfreactive thymocytes. Mature SP thymocytes
are exported from the thymus in response tocirculating sphingosine-1-phosphate (S1P).

Development of cortical and medullary
thymic microenvironments. The differentiation of TEC progenitor cells (pTEC) intofunctionally mature mTEC that express AIRE
and CCR7L is regulated by RANKL-expressing
lymphoid tissue inducer (LTi) cells during embryogenesis. In postnatal thymus, positive selection results in the generation of SP thymocytes that express RANKL and CD40L, which
promote the proliferation of mTEC andthereby nurture the formation of thymic medulla. Molecular mechanisms that regulate
the development of cTEC that express β5tcontaining thymoproteasomes is unknown,
but it is known that thymocyte development
to the DP stage affects the expansion of
cTEC to form the thymic cortex.

Hikosaka Y, Nitta T, Ohigashi I, Yano K, Ishimaru N, Hayashi Y, Matsumoto M, Matsuo K, Penninger JM,
Takayanagi H, Yokota Y, Yamada H, Yoshikai Y, Inoue J, Akiyama T, Takahama Y.
The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that
express autoimmune regulator.
Immunity. 29:438-450 (2008)
Murata S, Sasaki K, Kishimoto T, Niwa S, Hayashi H, Takahama Y, Tanaka K.
Regulation of CD8+ T cell development by thymus-specific proteasomes.
Science. 316:1349-1353 (2007)
Kurobe H, Liu C, Ueno T, Saito F, Ohigashi I, Seach N, Arakaki R, Hayashi Y, Kitagawa T, Lipp M, Boyd RL,
Takahama Y.
CCR7-dependent cortex-to-medulla migration of positively selected thymocytes is essential for establishingcentral tolerance.
Immunity. 24:165-177 (2006)
Takahama Y.
Journey through the thymus: stromal guides for T-cell development and selection.
Nature Rev Immunol. 6:127-135 (2006)

Keshavarz P, Inoue H, Nakamura N, Yoshikawa T, Tanahashi T, Itakura M.
Single nucleotide polymorphisms in genes encoding LKB1 (STK11), TORC2 (CRTC2)
and AMPK alpha2-subunit (PRKAA2) and risk of type 2 diabetes.
Mol Genet Metab. 9:200-209 (2008)
Extracted candidate genes:①ENDOGL1 gene, ②A novel gene, ③SOCS2 gene, ④UBR1 gene, ⑤MYL9 gene. Different Marks
show the different magnitude of linkage in the literature.

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Institute for Genome Research, The University of Tokushima

Institute for Genome Research, The University of Tokushima

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